Project Summary: Dr. Brendan Lucey, MD is a highly-motivated physician-scientist with a strong interest in sleep, aging, and neurodegenerative disorders such as Alzheimer's disease. He was recently promoted to Assistant Professor of Neurology (tenure track) at Washington University and is now seeking support for further mentorship as he focuses on a novel treatment strategy for Alzheimer's disease. Building on pioneering research at Washington University, Dr. Lucey is now studying how different sleep conditions (e.g. sleep deprivation, sleep induction with medication, normal sleep control) affect the central nervous system (CNS) production, clearance, and concentration of amyloid-? (A?). He has found that sleep deprivation significantly increases CNS A? and preliminary findings suggest that a similar increase in CNS A? occurs in individuals with poor sleep efficiency (i.e. poor sleep quality). Using a stable isotope labeled amino acid to determine in vivo A? production and clearance rates, Dr. Lucey will test: 1) if CNS A? production, clearance, and concentration are increased in individuals with poor sleep efficiency compared to those with good sleep efficiency; 2) if treating individuals with poor sleep efficiency treated with a sleep-inducing drug (suvorexant, a dual orexin receptor antagonist) will decrease CNS A? production, clearance, and concentration compared to controls. His short-term goals are to address fundamental and impactful questions of Alzheimer's disease and sleep by establishing an academic career, expanding his translational research group with independent funding (R01), and gain world-leading expertise in the understanding and treatment of sleep problems in older adults without and with neurodegenerative disorders such as Alzheimer's disease. Dr. Lucey's long-term goal is to develop an exciting research program investigating the interrelationships between sleep, aging, and Alzheimer's disease. Understanding these relationships could drive the development of new treatments to prevent or delay Alzheimer's disease. To accomplish these goals, he has enlisted an outstanding experienced investigator in aging research as mentor, Dr. Randall Bateman, as well as a career development advisory panel of international leaders in the fields of sleep research, geriatrics, aging, and Alzheimer's disease (Drs. Paul Shaw, David Holtzman, and David Carr). His career development plan includes: 1) frequent meetings with his mentor and advisory panel; 2) attendance and presentation at neurodegeneration, aging, and sleep focused seminars; 3) relevant coursework in clinical trial design, data management, aging, and mass spectrometry; 4) on-going training in the responsible conduct of research. Washington University School of Medicine has an outstanding track record of mentorship, in particular with K awardees, and has multiple labs focused on aging and neurodegenerative disorders. This will provide a rich and supportive scientific environment for mentorship in aging research. Dr. Lucey has ample (~400 square feet) laboratory space and equipment to accomplish this research project.